Abstract Diabetes mellitus (DM) and hypertension (HTN) are two prototypical vascular diseases associated with microscopic pathological changes in retinal capillary structure. These changes ultimately lead to capillary dysfunction, capillary closure, ischemia and vision loss. Current clinical methods and diagnostics for staging these diseases are neither effective in detecting the earliest capillary changes nor in detecting incremental capillary changes (improvement or worsening) in later stages of the disease. For example, clinical detection of capillary loss is generally not possible by clinical examination alone. Fluorescein angiography (FA) is an invasive test that has been traditionally used to assess retinal perfusion but human studies show that the resolution and technical limitations of FA is only effective in detecting capillary loss after ~50% or more of capillaries are already non-perfused. In addition, FA is not clinically indicated unless there are already clinical signs of late stage disease and neovascularization. Therefore, reliably detecting and characterizing subclinical retinal capillary changes in DM and HTN represents an important opportunity to decrease disease burden and cost by enabling early diagnosis, clinical trials and interventions before irreversible tissue damage. Optical coherence tomography angiography (OCTA) is a safe, non-invasive and FDA approved method that provides a unique opportunity to achieve these goals. Our group of physicians, scientists and engineers have been pioneers in the development and application of OCTA technology. In this proposal, we seek to shift the current research and clinical practice paradigms in assessment of retinal vascular disease by utilizing cutting-edge commercially available OCTA technology and novel image acquisition methods to identify and measure subclinical changes in capillary structure and function. Our preliminary data shows that subclinical capillary loss occurs in all stages of DR. In this proposal we will (1) further characterize capillary changes in well controlled, non-interventional clinical trial of human subjects across race, age, gender and other possible confounding variables by taking advantage of well-characterized subjects from NIH-funded population based studies. (2) Assess the feasibility and reliability of novel OCTA measures of retinal capillary function. (3) To further characterize the magnitude and physiological relevance of these capillary changes we will use a custom built functional swept-source OCTA (FOCTA) to assess real time and in vivo retinal vascular responses during a focal physiologic light stimulus. The successful outcome of this proposal will develop and implement novel SD- and SS-OCTA based technology in human subjects to identify novel biomarkers of capillary loss or closure in DM and HTN. Application of these biomarkers will improve the diagnosis and management of disease by allowing direct evaluation of capillary changes and ischemia in a clinical setting. Our proposal uses spectral domain (SD) and swept-source (SS)-OCTA devices that are FDA approved so our results will be directly transferable to patient care.